Cancer Treatment Reviews 39 (2013) 153160

Contents lists available at SciVerse ScienceDirect

Cancer Treatment Reviews

journal homepage: www.elsevierhealth.com/journals/ctrv

Laboratory-Clinic Interface

Evolving concepts in the management of drug resistant ovarian cancer: Dose

dense chemotherapy and the reversal of clinical platinum resistance
David J. Pinato a, Janet Graham b, Hani Gabra c, Rohini Sharma a,
a

Division of Experimental Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, W12 0HS London, UK
Department of Oncology, University of Glasgow, Glasgow, UK
c
Ovarian Cancer Action (HHMT) Research Centre, Imperial College London, Hammersmith Campus, Du Cane Road, London, UK
b

a r t i c l e

i n f o

Article history:
Received 4 March 2012
Received in revised form 13 April 2012
Accepted 17 April 2012

Keywords:
Ovarian cancer
Resistant
Relapse
Chemotherapy
Dose-dense
Platinum
Paclitaxel

a b s t r a c t
Despite the initially high response rate to standard front-line debulking surgery followed by platinumbased chemotherapy, the relapse rate in ovarian cancer is high and many patients will recur within
6 months of completing platinum based treatment. These patients may still require further chemotherapy despite being considered platinum resistant. In this setting, response rates to conventionally scheduled second line platinum and non-platinum agents is low, ranging between 5% and 15%. There is an
emerging body of evidence that in this scenario, chemotherapeutic activity can be enhanced using unconventionally scheduled dose-dense platinum and non-platinum based regimens with improved
response rates of up to 65%. Randomised studies to evaluate the impact of this approach on survival in
recurrent, platinum resistant disease are urgently required to conrm the promising phase II ndings
if there is to be a change in the standard of care of patients with platinum resistant disease. In this review
we discuss the evolving strategies to overcome resistance in patients with platinum resistant ovarian
cancer with a particular focus on alterations in dose schedule as a means of reversing platinum resistance.
2012 Elsevier Ltd. All rights reserved.

Ovarian cancer and clinical platinum resistance

Ovarian cancer is the leading cause of death from gynaecologic
malignancies in the United Kingdom, the United States and most of
Western Europe. The standard treatment for patients with
advanced (FIGO stage IC-IV) disease is initial debulking surgery
followed by 3 weekly carboplatin-paclitaxel combination chemotherapy resulting in a median progression-free survival of up to
22 months and a median overall survival of up to 57 months for
optimally debulked patients.1 The survival rates are lower in patients who have not had completed macroscopic cytoreduction at
initial surgery and the 5-years overall survival rates in this setting
are closer to 40%.2,3 The superior efcacy of 3 weekly carboplatinpaclitaxel over other cytotoxic regimens either single agent, doublet or triplet has remained an unchallenged concept for more
than 10 years.2,47 More recently, however, the addition of bevacizumab, a monoclonal antibody against vascular endothelial
growth factor (VEGF), has shown additional progression free survival benet in two randomised phase III studies particularly in
those patients at high risk of recurrence (i.e. FIGO Stage IV or III
with macroscopic residual disease).8,9 Furthermore, a recent publication suggests that the administration of 3 weekly carboplatin in
Corresponding author. Tel.: +44 20 83833720.
E-mail address: r.sharma@imperial.ac.uk (R. Sharma).
0305-7372/$ - see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ctrv.2012.04.004

combination with weekly paclitaxel (80 mg/m2) results in a 30%

improvement in PFS compared to standard 3 weekly dose scheduling, a concept which is further explored within this review.10
However, despite these advances in the delivery of front-line
chemotherapy many patients will either not respond or their disease will relapse predominantly due to the emergence of platinum
resistant disease, a key concept in the management of ovarian cancer that is explored in detail in this review.
When ovarian cancer relapses the aim of therapy changes from
one of potential cure to that of chronic disease management; prolonging survival, maximising quality of life, preventing or reducing
complications and ensuring good symptom control. For patients
with recurrent disease, the judicious use of systemic therapies
including chemotherapy is important. The time interval between
the completion of rst line treatment and relapse is the most
important predictive factor for the likelihood of responding to second-line therapy, and the selection of an appropriate chemotherapeutic agent in the relapse setting depends in part on this
treatment free interval.
It is well established that platinum agents are the most active
drugs in the treatment of recurrent disease. The probability of
response to rechallenge with platinum agents depends on the time
from cessation of last platinum therapy to initiation of the next
chemotherapy, termed the platinum free interval (PFI).
Moreover, the PFI not only predicts the probability of subsequent

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D.J. Pinato et al. / Cancer Treatment Reviews 39 (2013) 153160

response to second line treatment with platinum based chemotherapy but also to other active agents in ovarian cancer including
the taxanes, topoisomerase inhibitors and anthracyclines.11 Data
from retrospective studies suggest that PFI is a continuum, with
increasing response probability as time beyond 6 months
increases.1214 Although current convention holds that patients
relapsing more than 6 months after rst therapy are termed platinum-sensitive, it is not until the PFI is 1824 months that the
probability of response to second-line platinum approaches that
of the platinum nave patient. Much debate surrounds the adoption
of these intervals into clinical trials.
Patients relapsing within 6 months are regarded as being resistant to conventional schedule platinum, and within this category is
a smaller group who progress on front line therapy, dened as
refractory. Platinum resistant/refractory ovarian cancer represents
a different clinical scenario with a much lower (<10%) response rate
to re-treatment with conventional platinum chemotherapy.1215
Generally, platinum resistant tumours are treated with non-platinum agents such as pegylated liposomal doxorubicin 4 weekly,
topotecan 3 weekly, paclitaxel 3 weekly or oral etoposide, all
administered as monotherapies.11,16,17 Response rates to these
agents are low ranging between 8% and 15%, with durations of response similarly brief although phase II studies using some of these
agents in combinations show some promise.1619 Treatment decisions are therefore made with reference to the convenience of drug
administration, expected toxicity prole and quality of life.
There is increasing evidence that the alteration of chemotherapeutic dosing schedule may increase response rates in platinum
resistant disease. In particular, platinum delivered weekly rather
than 3 weekly, in a dose dense fashion, with or without other
drugs, may overcome proven clinical resistance to standard-schedule platinum, resulting in signicant improvements in response.20
In this review we will rstly discuss the concept of dose and schedule manipulation in the context of platinum resistant disease, and
critically evaluate the published studies in this area. We will then
consider future studies that need to be conducted in order to dene
whether dose dense therapy may improve outcomes in platinum
resistant ovarian cancer and, on the assumption that this approach
is not inferior to standard therapies, introduce the concept of a
dose-dense platinum scaffold into which other novel resistance-reversing targeted therapies can be incorporated.

Biological basis of increased activity in dose dense therapy

For a number of cytotoxics, it is accepted that increased frequency of chemotherapy administration may reduce toxicity and
increase efcacy. This concept is in routine clinical practice for
drugs such as continuous infusional 5-uorouracil/capecitabine,
and oral etoposide where there are clear advantages for schedule
changes.21,22 The mechanistic basis for these benets is unclear
but it has been postulated to involve Gompertzian models of chemotherapy re-growth and anti-angiogenic mechanisms.23,24 Early
work assumed that human solid tumours grow in an exponential
fashion and conversely, that the rate of chemotherapy-induced tumour regression would be proportional to the rate of growth. The
SkipperSchabelWilcox (log-kill) model hypothesised that given
enough cycles of sufciently dosed chemotherapy, a high percentage, if not all, of the tumour cells should be killed.25 This model did
not fully describe the in vivo situation and led to an alternative
model of cancer growth based on Gompertzian growth kinetics,
where cells attain a plateau phase of slow growth as the tumour
bulk increases.26 Small tumours therefore grow faster than large
ones, because intrinsically they have a higher proliferation rate
(the NortonSimon hypothesis). The effect of cytotoxic chemotherapy then is to shrink these small volume tumours and render these

tumours cells into the sensitive part of the cell cycle.27 More frequent drug administration would therefore be an effective way
of reducing tumour burden, and may potentially limit re-growth
of resistant cell populations.
As will be shown altering the dose delivery regimen does increase activity, and although limited, there is some evidence from
both breast and ovarian cancer that this translates into improved
overall survival. Conversely, there is clearer evidence that compromised dose intensity through dose reductions and delays results in
poorer treatment outcomes. However, it is also clear that traditional high dose chemotherapy approaches in the absence of schedule change provide no benet in ovarian cancer.28

Dose intensity and dose density

Dose intensity is dened as the amount of drug administered
per unit of time (typically mg/m2/week), and can be increased in
a number of ways.29 Firstly, the dose delivered per cycle can be increased (dose intensity), secondly, the dosing interval can be reduced keeping the dose per cycle and overall dose the same
(dose density), and nally both the dosing interval can be reduced
and the overall dose increased, resulting in an increase in dose
intensity, total dose, and dose density.
The concept of dose manipulation, in particular the delivery of
dose dense chemotherapy is not novel and has been extensively
studied in a number of tumour types particularly breast cancer.
The CALGB 9741 study is a pivotal paper in the study of dose density.30 The study used a 2  2 factorial design in which women
with node-positive breast cancer were randomly assigned to
sequential doxorubicin, paclitaxel and cyclophosphamide or concurrent doxorubicin/cyclophosphamide followed by paclitaxel
delivered in either a 2 weekly (dose dense) or 3 weekly schedule.
Signicant improvement in disease free survival and overall survival was reported in the dose dense 2 weekly arms compared to
the 3 weekly arms, with an acceptable side-effect prole, in particular less grade 4 myelosuppression. The efcacy of dose dense
therapy has been further supported by a number of smaller randomised studies in head and neck and lung cancer.31,32
The molecular mechanisms for the observed advantage in cell
kill and tumour response associated with increased schedule frequency and dose dense therapy are not well described. For S-phase
targeting agents, preclinical data suggests that shorter cycle
lengths may be more advantageous as more cells are exposed to
the drug during the sensitive phase of the cell cycle. This may result in a reduction in the proportion of cells in G0, a reduction in
resistance signalling associated with intercellular and cell to matrix adhesion, and possibly inhibition of anoikis.3336 When combined with maximisation of tolerated dose, increasing the dose
frequency may well overcome resistance mechanisms generated
in response to conventionally dosed and scheduled regimens.
Another process that may be targeted by increased schedule
frequency is tumour associated neo-angiogenesis. This has been
proposed as the predominant mechanism of action of cytotoxics
administered on a weekly basis including paclitaxel and 5FU.37,38 Although different to dose dense therapy, a frequent scheduling approach termed metronomic chemotherapy may inform
about the potential mechanism of action of dose dense therapy.39
Metronomic chemotherapy is dened as the frequent administration of continuous, low doses of cytotoxic chemotherapy at
frequent intervals, to inhibit angiogenesis. The rationale is based
on the notion that DNA damage or microtubule disruption may
preferentially target endothelial cell division during tumour neoangiogenesis. In experimental models, this approach inhibits angiogenesis and suppresses tumour growth by stimulating the release
of thrombospondin.40 Most recently this was investigated in a

D.J. Pinato et al. / Cancer Treatment Reviews 39 (2013) 153160

non-randomised phase II study of low-dose metronomic cyclophosphamide combined with bevacizumab in a heavily pretreated
patient population with recurrent ovarian cancer, 80% of which
had platinum resistant disease.41 This study reported a response
rate of 24%, however, the response according to PFI was not reported and there were also a signicant number of episodes of bowel perforation. Metronomic therapy may therefore inform about
an interesting potential facet of dose dense therapy, that of enhanced anti-angiogenesis compared with conventionally scheduled therapy, which may contribute to the clinical benet of this
approach.
What is the evidence to support dose dense therapy for
platinum resistant ovarian cancer?
The approaches to dose manipulation described above have
been explored in ovarian cancer, and there is an emerging body
of evidence that platinum based therapy delivered in a dose dense
fashion may overcome platinum resistance. Moreover, the use of a
dose dense strategy may allow for the integration of potential novel targeted therapies with platinum. This would allow for the continued use of platinum in recurrent ovarian cancer.
Dose intensity: how much is enough?
In vitro studies in platinum resistant ovarian cancer illustrate a
limited doseresponse relationship with cisplatin.42 Extrapolating
from this then is the suggestion that increasing the dose of cisplatin clinically may circumvent drug resistance. However, the
concept of dose intensity has not been borne out successfully in
the clinical setting.29 Review of the published studies investigating
dose intensity indicates that the majority of studies were only able
to deliver a twofold increase in platinum dose, and that higher
doses were not achievable without signicant toxicity, and with
no benet to clinical outcomes.28,43 Substantial toxicity was reported in these studies particularly renal, bone marrow and
neuro-toxicity precluding the use of this approach. Furthermore,
in almost all studies, no survival advantage was reported.29,44,45
Therefore, increasing dose intensity beyond a certain optimum
through just increasing the dose is ineffective in ovarian cancer.
However, the delivery of very high local dose intensity through
intraperitoneal (IP) chemotherapy has shown clinical benet.
The role and benet of IP therapy currently is restricted to optimally debulked chemo nave ovarian cancer. Currently, there is no
evidence to suggest that IP therapy should be used in platinum
resistant, recurrent ovarian cancer. However, as an approach to
achieving dose intensity, further discussion about IP therapy is
warranted. IP therapy allows ovarian cancer cells to be locally exposed to higher doses of chemotherapy than would otherwise be
possible with systemic therapy. Several trials have shown
improved survival for patients receiving IP treatment.4648 However, the interpretation of the results of these studies is widely debated. Of particular contention is whether the survival benet seen
in the IP arms is ascribable to enhanced effectiveness of IP dosing
or whether it is due to increased systemic exposure of chemotherapy, including schedule changes to paclitaxel in some of the studies.49 Overall, our view, and that of many others, is that there is
probably a benecial effect from IP therapy, but that its magnitude
has been overstated.50 This underscores the sense that it is not only
dose but also schedule that contributes to effective cell kill with
cytotoxic therapy. Nevertheless many clinicians feel that until an
IP regimen has shown superiority over a directly comparable intravenous (IV) regimen, and that the considerable toxicity issues are
addressed, IP therapy remains investigational and further investigation of IV drug scheduling and combinations are warranted. PET-

155

ROC/OV21 is a proposed study that once completed will further

dene the role of IP therapy in ovarian cancer. The study proposes
to directly evaluate whether IP therapy is superior to standard
therapy in patients who are optimally debulked followed delayed
primary surgery. The role of IP therapy that combines platinum
and targeted therapeutics that reverse platinum resistance are entirely unexplored either in front line therapy or in recurrent disease of platinum sensitive or resistant type and this remains an
area of interest.
Dose dense therapy: Does giving enough with reduced time interval
lead to benet?
As discussed above, the use of combination chemotherapy in
resistant disease is generally not routinely advocated, and a reasonable standard of care is considered to be pegylated liposomal
doxorubicin.51,52 However, with a response rate to liposomal doxorubicin in the platinum resistant patient group of 12%, there is
clearly a need to develop more effective regimens.
Etoposide has been shown to be effective in the treatment of
platinum-resistant ovarian cancer, with reported response rates
of up to 25%.53 Based on this, and on previous work suggesting synergy between etoposide and cisplatin, van der Burg and colleagues
pioneered the initial dose dense studies in recurrent ovarian cancer.5456 They delivered a short duration induction of 6 weekly
cycles of cisplatin 70 mg/m2 day 1, 8, 15 and 29, 36, 43 combined
with daily oral etoposide 50 mg/m2 on days 115 and days 2943.
Etoposide 50 mg/m2 was continued for 21 days, q4weekly in those
patients responding to platinum therapy. Of 98 patients, the 32
who were platinum resistant/refractory had a 46% response rate
to dose dense therapy. These results were essentially replicated
simultaneously in a retrospective study utilising weekly cisplatin
60 mg/m2 and daily oral etoposide in patients with platinum resistant disease.57 However, in both studies the treatment regimen
was not well tolerated, with patients experiencing a high incidence
of grade 3/4 myelosuppression, nephrotoxicity, emesis, ototoxicity
and neurotoxicity. Signicant numbers of patients experienced
dose delays secondary to toxicity potentially negating the impact
of the dose dense schedule. Furthermore, the dose dense phase
was limited to only 6 weekly cycles of cisplatin. These results are
supported by a number of other smaller studies reporting response
rates of 6070% to weekly cisplatin monotherapy in the second and
third line setting in ovarian cancer.5860 However, a phase III randomized trial in the rst-line setting, exploring the efcacy of
weekly single agent cisplatin 50 mg/m2 versus a 3 weekly regimen
75 mg/m2 in patients with advanced epithelial ovarian cancer
failed to report any improvement in overall and progression free
survival induced by dose intensication.61 These results differ to
those reported by Katsumata and colleagues who compared the
efcacy of weekly paclitaxel 80 mg/m2 with 3-weekly paclitaxel
180 mg/m2 in combination with carboplatin AUC 6 3 weekly in
patients with advanced ovarian cancer in the front-line setting.10
The authors report both an improvement in both PFS and OS with
the administration of dose dense paclitaxel. The positive results
observed in the Katsumata paper may reect an increased antiangiogenic effect of weekly paclitaxel or to the elimination of an
antagonistic interaction with platinum62,63 An interesting question
that arises from these studies is why dose dense platinum appears
to be efcacious in the setting of platinum resistance but not in the
management of platinum sensitive disease. This may in part
pertain to the chemotherapeutic agents used in previous studies
or may be a reection of the altered biology of the platinum resistant phenotype. The planned MITO 7 study (trial registration:
NCT00660842) will compare carboplatin AUC 5 plus paclitaxel
175 mg/m2 3-weekly with weekly carboplatin AUC 2 plus weekly
paclitaxel 60 mg/m2 will further dene the role of weekly platinum

156

Table 1
Studies of weekly paclitaxel and carboplatin in platinum resistant recurrent ovarian cancer.
Regimen

Platinum
sensitivity

RR
(%)

CR
(%)

PFS
(months)

OS
(months)

Van der
Burg54

T 90 mg/m2/wk

Total
number
<6 m
612 m
>12 m
Total
number
<6 m
612 m
>12 m

62

74

24

11

NR

23
19
20
29

61
84
80
66

13
42
20
21

18

10
11
8

38
73
80

13
18
30

8
NR
NR

29

83

55

6.8
10.5
12.8
2.6
11.5

8
21

38
100

13
71

3.2
13.7

11.4

21

60

7.9

5
7
9
20

25
25
50
85

75

5
5
10
165

60
93

40
87

37

10

Cadron55

C AUC 4/wk
D1, 8, 15, 29, 36, 49
+6xTC q3w
T 90 mg/m2/wk
C AUC 4/wk
D1, 8, q3w
6 courses

Havrilesky57

T 80 mg/m2/wk

Sharma64

C AUC 2/wk
D1, 8, 15 q28d until progression/CR + 8
courses
T 70 mg/m2/wk

Hoekstra75

C AUC 3/wk
D1, 8, 15 q4w
46 courses
T 80 mg/m2/wk
C AUC 3/wk

Lortholary74

Arm 1:T 80 mg/m2/wk D1, 8,

15 q4w
Arm 2: T 80 mg/m2/wk D1, 8,
15 q4w + C AUC 5 q4w
Arm 3: T 80 mg/m2/wk D1, 8, 15
q4w + topotecan 3 mg/m2 D1, 8, 15 q4w
69 courses

Total
number
<6 m
>6 m
Total
number
Refractory
<6 m
>6 m
Total
number
<6 m
612 m
>12 m
Total
number
Refractory
<3 m
36 m

2
78
85

Anaemia
(%)

Neutropaenia

Thrombocytopaenia

Neurotoxicity

Alopecia

Hypersensitivity

40

24

94

25

11

32

14

21

13.3

30

15

NR

14

8.9
5.5
7.8
-

6.8

10.0

35

25

3.7*

19.9**

18

36

28

43

4.8
5.4

15.2
18.6

23

Toxicity is grade P3 and expressed in %, N: number of patients, m: months, wk: weeks, RR: response rate, CR: complete remission, PFS: progression free survival, OS: overall survival, T: paclitaxel, C: carboplatin, NR: not reached.
Adapted from Cadron.55
*
Median PFS given for Arm, 2 and 3.
**
Overall survival given for Arm, 2 and 3.

D.J. Pinato et al. / Cancer Treatment Reviews 39 (2013) 153160

Study

T 8090 mg/m /wk, 1824 weeks

Linch

Toxicity is grade P3 and expressed in %, N: number of patients, m: months, wk: weeks, RR: response rate, CR: complete remission, PFS: progression free survival, OS: overall survival, T: paclitaxel, C: carboplatin, NR: not reached.
Adapted from Cadron.55

28
8
53
10
14

41

19

13.5

3
4
50
20.9
T 80 mg/m2/wk
T 80 mg/m2/wk

2
73

Boruta

Ghamande71
Markman67

T 80 mg/m /wk

2
70

T 80 mg/m2/wk, 6 weeks on, 2 weeks for 3 cycles

Dunder69

Platinum and paclitaxel

resistant
Total number
<30 m taxane
>30 m taxane

22
15
7
28
48

NR

27

NR
14

10.5
NR
3
31
14
23
32

<6 m platinum
>6 m platinum
Platinum and paclitaxel
resistant
Total number
<6 m platinum
>6 m platinum

T 6781 mg/m2/wk
T 80 mg/m2/wk days 1, 8, 15 q28 days until disease progression or sideeffects
Rosenberg66
Kita68

12
2

6
9
104
37

36
25

16.7

26
NR

21

3
0
5
24
22
3
12
25
56
53
18
39
T 80 mg/m2/wk until disease progression or side-effects
T 80 mg/m2/wk
Markman72
Kaern65

Platinum resistant
Platinum resistant
Platinum and paclitaxel
resistant
54% Platinum resistant
Total number

Regimen
Study

Table 2
Studies of weekly paclitaxel in platinum resistant recurrent ovarian cancer.

Population

RR
(%)

CR
(%)

PFS
(weeks)

OS
(months)

Anaemia

Neutropaenia

Neurotoxicity (2/
3)

D.J. Pinato et al. / Cancer Treatment Reviews 39 (2013) 153160

157

regimen in the front-line setting using drugs that are the current
standard.
Weekly cisplatin/paclitaxel has also been evaluated in patients
with advanced ovarian cancer.64 In this study patients received 6
weekly cycles of cisplatin 70 mg/m2 combined with escalating
doses of paclitaxel, administered either 4-weekly (135225 mg/
m2) or weekly (60100 mg/m2), followed by 3-weekly paclitaxel/
platinum therapy. In this trial, in the ten patients with platinum
refractory disease a response rate of 64% was reported with a median progression free survival of 8 months and a median overall survival of 10 months. However, again, as with the other combination
therapies described, this regimen was limited by high incidence of
myelosuppression in particular grade 3/4 neutropaenia and
thrombocytopaenia.
In view of the signicant toxicity encountered with dose dense
cisplatin, further studies substituting carboplatin for cisplatin were
undertaken. These studies all differ in the dose intensity of carboplatin and paclitaxel administered, duration of therapy, and concurrent toxicity.6573 Furthermore, only four of the nine published
studies enrolled patients with platinum resistant disease (Table 1).
The largest of these studies by de Jongh and colleagues reported a
response rate of 61% in a subgroup of 23 patients with platinum
resistant/refractory disease receiving carboplatin AUC 4 and paclitaxel 90 mg/m2 day 1, 8, 15 for two cycles followed by 6 courses of 3
weekly carboplatin/paclitaxel.20 The dose-dense component of this
study was used as an induction regimen with responding patients
subsequently treated with conventional therapy. It is also important to note that carboplatin single agent given weekly cannot be
given at a dose higher than AUC (2) due to thrombocytopenia,
and that it was the thromboprotective effect of paclitaxel that allowed the higher AUC of 4 to be given in this study.74
This thromboprotective effect of paclitaxel has been demonstrated previously, in the ICON4 clinical trial of carboplatin versus
carboplatin and paclitaxel in platinum sensitive recurrent ovarian
cancer.75 In this study the grade 34 haematological toxicity was
46% for the carboplatin only arm as compared with only 29% for
the carboplatin and paclitaxel arm despite identical carboplatin
exposure for patients. A recent study by our group in patients
with platinum resistant disease explored the activity and tolerability of an extended dose dense regimen utilising carboplatin
(AUC3) and paclitaxel 70 mg/m2 days 1, 8, 15, q28 days for six cycles.76 We reported a response rate of 60% in 20 patients, similar
to previously published studies, with high tolerability and a low
incidence of grade 3/4 febrile neutropaenia, with no grade 3/4
thrombocytopaenia.76
For non-platinum agents, perhaps the most studied in platinum
resistant disease with regards to schedule change is paclitaxel with
nine studies published including a large phase III trial7785 (Table
2). The rationale of weekly paclitaxel is based on in vitro studies
that suggest that fractionated, short infusion schedules may be
more effective than the standard 3 h/3weekly infusions as more
cells are exposed to the drug during the sensitive phase of the cell
cycle, and as discussed, there may be additional anti-angiogenic effects.37,38 The largest randomised trial compared a 3 weekly versus
weekly schedule of paclitaxel in 208 patients with ovarian cancer
previously treated with a platinum agent, and demonstrated no
difference in response rate or time to progression or survival but
less toxicity in the weekly arm.78 However, the trial was stopped
early because of poor accrual, and this may have impacted on reported results. Reported phase II studies suggest response rates between 25% and 50%, however the disease characteristics of study
populations were not always reported particularly platinum and
taxane free intervals. However, combination schedules including
weekly paclitaxel do not seem to improve outcome in platinum
resistant ovarian cancer. Interestingly, results from a recent randomized phase II trial comparing the efcacy of weekly paclitaxel

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D.J. Pinato et al. / Cancer Treatment Reviews 39 (2013) 153160

80 mg/m2 alone or in combination with monthly carboplatin

(AUC5) or weekly topotecan 3 mg/m2 showed no benet in terms
of radiological response or progression free survival in spite of majorly increased grade 3/4 toxicities in the doublet arms.86 Similar
response rates to those reported in our study were observed by
Hoekstra et al. where 20 patients with stage IC-IV recurrent ovarian cancer were treated with monthly carboplatin (AUC5) day 1
and weekly paclitaxel 80 mg/m2 days 1, 8, 15, q28 days for six cycles. The response rate in platinum sensitive patients was 93%
compared to 60% achieved by platinum resistant.87 Neutropenia
was the only grade 3/4 adverse event, occurring in 35% of the
patients.

Dose dense platinum regimens as a scaffold for integration of

targeted therapies that reverse platinum resistance
Based on these results, it may be possible to create an active
dose dense platinum scaffold that can be used to integrate novel
agents that target the reversal of platinum resistance. The role of
the paclitaxel in this scaffold is twofold, rstly to impart a cytotoxic effect, and secondly to improve the feasibility of carboplatin
by virtue of the thromboprotective effect.74 Whilst it is possible to
deliver AUC 3 carboplatin weekly for 18 cycles, the next question is
what is the minimum dose of paclitaxel required to be thromboprotective? The reason for this is that strategies that seek to reverse platinum resistance specically may choose to maximise
delivered weekly platinum, and also maximise space within the
scaffold. The maximisation of space hypothetically would allow
the accommodation of potential toxicities of targeted molecular
therapies administered either singly or in combination (since platinum resistance is due to multiple molecular factors) since these
novel agents are sure to bring their own toxicities to any regimen.
A good example of this scaffold strategy is to be found in two clinical trials combining dose dense chemotherapy with the isoavone
derivative, phenoxodiol (PXD). PXD induces apoptosis in vitro and
in vivo, and may act at least in part through indirect inhibition of
the AKT pathway.88 PXD has been shown to act as a chemosensitising agent, when given with either the platinums or taxanes.
In the phase II study by Kelly et al. intravenous phenoxodiol was
tested in combination with weekly paclitaxel or cisplatin89 This
study enrolled 31 patients who had become resistant to taxanes
or platinum either as single agents or in combination and allocated
them to receive PXD 3 mg/kg weekly on days 1 and 2 in combination with either weekly paclitaxel (n = 15) or cisplatin (n = 16). The
toxicity prole emerging from both arms was essentially in line
with that of previously published studies on weekly paclitaxel
and cisplatin and the reported overall response rate was 20%. Despite the studied schedule was proven to be safe and active in
chemoresistant ovarian cancer, the lack of an appropriate control
arm in this study makes however impossible to interpret whether
the addition of PXD to systemic chemotherapy holds any synergistic cytotoxic effects.
The recently completed OVATURE phase III trial tested the efcacy of weekly carboplatin with or without PXD. Patients relapsing
within 6 months of second or subsequent relapse after conventional platinum were randomised to weekly carboplatin AUC 2 +/
PXD orally, daily. Unfortunately the combination treatment did
not conrm a statistically signicant improvement in the primary
(progression-free) or secondary (overall survival) endpoints of the
study, leading to a premature discontinuation of the study in June
2010 (unpublished data).
In spite of the lack of efcacy observed for PXD in this context,
this trial conrms the validity and safety of combining a putative
platinum resistance reversing agent with altered scheduling of
platinum, in patients with proven platinum resistance. Therefore,

boosting the dose intensity of carboplatin using paclitaxel thromboprotection may establish the rationale for this cytotoxic approach.
Previous experience from our institution shows that this combination approach is safe and feasible in chemoresistant ovarian cancer. The use of low dose paclitaxel (20 mg/m2) together with
weekly dose dense carboplatin AUC 3 is associated with a tolerable
antiplatelet toxicity prole.90 Based on these preliminary safety
data one can then consider how to approach targeted platinum
resistance reversal to begin to build treatments that are effective
in managing platinum resistant recurrence of ovarian cancer.
Conclusions
Dose dense approaches demonstrate a step change in cytotoxic
activity in the management of ovarian cancer, both in the rst line
and in the second line setting.
The biological mechanisms by which dose dense therapy works
is not entirely clear. As discussed, angiogenesis may be an important target of dose dense therapy, and it may be that these mechanisms are signicant in the development of clinical platinum
resistance.
Dose dense regimens can be further developed as scaffolds for
the integration of molecular targeted therapies particularly those
directed at reversal of platinum resistance. Clearly, the discovery
of novel biomarkers mediating platinum resistance in vivo is felt
as a priority to enable the full development of personalized oncology and the characterization of targets amenable to pharmacological intervention. The lack of efcacy seen in the OVATURE trial
increases the importance of translational, biomarker-driven phase
II studies to test novel strategies to address platinum resistance.
Furthermore, the choice of a randomized controlled study design
is mandatory in order to suitably test differences in response rates
and survival.
Despite the acceptable toxicity proles and the encouraging response rates observed, it is important however to remember that a
dose dense approach brings with it some inconvenience to patients
with weekly attendance for chemotherapy. Both cost effectiveness
and quality of life analyses are therefore necessary to critically
evaluate whether this approach will be worthwhile for patients
undergoing palliative treatment even if clear clinical benets are
observed.
References
1. du Bois A, Luck HJ, Meier W, Adams HP, Mobus V, Costa S, et al. A randomized
clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as rst-line
treatment of ovarian cancer. J Natl Cancer Inst 2003;95:13209.
2. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al.
Cyclophosphamide and cisplatin versus paclitaxel and cisplatin: a phase III
randomized trial in patients with suboptimal stage III/IV ovarian cancer (from
the Gynecologic Oncology Group). Semin Oncol 1996;23:407.
3. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al.
Phase III trial of carboplatin and paclitaxel compared with cisplatin and
paclitaxel in patients with optimally resected stage III ovarian cancer: a
Gynecologic Oncology Group study. J Clin Oncol: Off J Am Soc Clin Oncol
2003;21:3194200.
4. Bookman MA, Brady MF, McGuire WP, Harper PG, Alberts DS, Friedlander M,
et al. Evaluation of new platinum-based treatment regimens in advanced-stage
ovarian cancer: a Phase III Trial of the Gynecologic Cancer Intergroup. J Clin
Oncol: Off J Am Soc Clin Oncol 2009;27:141925.
5. Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, et al.
Randomized intergroup trial of cisplatinpaclitaxel versus cisplatin
cyclophosphamide in women with advanced epithelial ovarian cancer: threeyear results. J Natl Cancer Inst 2000;92:699708.
6. Piccart MJ, Bertelsen K, Stuart G, Cassidy J, Mangioni C, Simonsen E, et al. Longterm follow-up conrms a survival advantage of the paclitaxelcisplatin
regimen over the cyclophosphamidecisplatin combination in advanced
ovarian cancer. Int J Gynecolo Cancer: Off J Int Gynecol Cancer Soc
2003;13(Suppl. 2):1448.
7. Kyrgiou M, Salanti G, Pavlidis N, Paraskevaidis E, Ioannidis JP. Survival benets
with diverse chemotherapy regimens for ovarian cancer: meta-analysis of
multiple treatments. J Natl Cancer Inst 2006;98:165563.

D.J. Pinato et al. / Cancer Treatment Reviews 39 (2013) 153160

8. Perren TJ, Swart AM, Psterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G,
et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med
2011;365:248496.
9. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al.
Incorporation of bevacizumab in the primary treatment of ovarian cancer. N
Engl J Med 2011;365:247383.
10. Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, et al. Dosedense paclitaxel once a week in combination with carboplatin every 3 weeks
for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial.
Lancet 2009;374:13318.
11. Eisenhauer EA, Vermorken JB, van Glabbeke M. Predictors of response to
subsequent chemotherapy in platinum pretreated ovarian cancer: a
multivariate analysis of 704 patients see comments. Ann Oncol 1997;8:9638.
12. Blackledge G, Lawton F, Redman C, Kelly K. Response of patients in phase II
studies of chemotherapy in ovarian cancer: implications for patient treatment
and the design of phase II trials. Br J Cancer 1989;59:6503.
13. Markman M, Rothman R, Hakes T, Reichman B, Hoskins W, Rubin S, et al.
Second-line platinum therapy in patients with ovarian cancer previously
treated with cisplatin. J Clin Oncol: Off J Am Soc Clin Oncol 1991;9:38993.
14. Gore ME, Fryatt I, Wiltshaw E, Dawson T. Treatment of relapsed carcinoma of
the ovary with cisplatin or carboplatin following initial treatment with these
compounds. Gynecol Oncol 1990;36:20711.
15. Colombo N, Gore M. Treatment of recurrent ovarian cancer relapsing 6
12 months post platinum-based chemotherapy. Crit Rev Oncol Hematol
2007;64:12938.
16. Hoskins PJ, Swenerton KD. Oral etoposide is active against platinum-resistant
epithelial ovarian cancer. J Clin Oncol: Off J Am Soc Clin Oncol 1994;12:603.
17. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent
epithelial ovarian carcinoma: a randomized phase III study of pegylated
liposomal doxorubicin versus topotecan. J Clin Oncol: Off J Am Soc Clin Oncol
2001;19:331222.
18. Bruzzone M, Centurioni MG, Giglione P, Gualco M, Merlo DF, Miglietta L, et al.
Second-line treatment with intravenous gemcitabine and oral etoposide in
platinum-resistant advanced ovarian cancer patients: results of a phase II
study. Oncology 2011;80:23846.
19. Crespo G, Sierra M, Losa R, Berros JP, Villanueva N, Fra J, et al. Pegylated
liposomal doxorubicin and gemcitabine in a xed dose rate infusion for the
treatment of patients with poor prognosis of recurrent ovarian cancer: a phase
Ib study. Int J Gynecol Cancer: Off J Int Gynecol Cancer Soc 2011;21:47885.
20. van der Burg ME, van der Gaast A, Vergote I, Burger CW, van Doorn HC, de Wit
R, et al. What is the role of dose-dense therapy? Int J Gynecol Cancer: Off J Int
Gynecol Cancer Soc 2005;15(Suppl. 3):23340.
21. Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA, Fryer JG. A prospective randomized
comparison of continuous infusion uorouracil with a conventional bolus
schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program
Study. J Clin Oncol: Off J Am Soc Clin Oncol 1989;7:42532.
22. Slevin ML, Clark PI, Joel SP, Malik S, Osborne RJ, Gregory WM, et al. A
randomized trial to evaluate the effect of schedule on the activity of etoposide
in small-cell lung cancer. J Clin Oncol: Off J Am Soc Clin Oncol 1989;7:
133340.
23. Norton L. Evolving concepts in the systemic drug therapy of breast cancer.
Semin Oncol 1997;24:S3S10.
24. Hudis CA. Clinical implications of antiangiogenic therapies. Oncology (Williston
Park) 2005;19:2631.
25. Skipper HE. Laboratory models: some historical perspective. Cancer Treat Rep
1986;70:37.
26. Norton L, Simon R, Brereton HD, Bogden AE. Predicting the course of
Gompertzian growth. Nature 1976;264:5425.
27. Norton L. A Gompertzian model of human breast cancer growth. Cancer Res
1988;48:706771.
28. Mobus V, Wandt H, Frickhofen N, Bengala C, Champion K, Kimmig R, et al. Phase
III trial of high-dose sequential chemotherapy with peripheral blood stem cell
support compared with standard dose chemotherapy for rst-line treatment of
advanced ovarian cancer: intergroup trial of the AGO-Ovar/AIO and EBMT. J Clin
Oncol: Off J Am Soc Clin Oncol 2007;25:418793.
29. Vasey PA. Dose dense chemotherapy in ovarian cancer. Int J Gynecol Cancer:
Off J Int Gynecol Cancer Soc 2005;15(Suppl. 3):22632.
30. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al.
Randomized trial of dose-dense versus conventionally scheduled and
sequential versus concurrent combination chemotherapy as postoperative
adjuvant treatment of node-positive primary breast cancer: rst report of
Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol:
Off J Am Soc Clin Oncol 2003;21:14319.
31. Ho KF, Swindell R, Brammer CV. Dose intensity comparison between weekly
and 3-weekly cisplatin delivered concurrently with radical radiotherapy for
head and neck cancer: a retrospective comparison from New Cross Hospital,
Wolverhampton. UK Acta Oncol 2008;47:15138.
32. Kallab AM, Nalamolu Y, Dainer PM, Jillella AP. A phase II study of weekly
paclitaxel and carboplatin in previously untreated patients with advanced nonsmall-cell lung cancer. Med Oncol 2005;22:14551.
33. Teicher BA. Hypoxia and drug resistance. Cancer Metastasis Rev
1994;13:13968.
34. Bence AK, Mattingly CA, Desmione PA, Doukas MA, Adams VR. Evaluation of
topotecan cytotoxicity and topoisomerase I levels in non-small cell lung cancer
cells. In: 93rd Annual meeting of the American Association for Cancer Research.
San Francisco, CA; 2002 abstr 1227a.

159

35. Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C, et al.
Extracellular matrix proteins protect small cell lung cancer cells against
apoptosis: a mechanism for small cell lung cancer growth and drug resistance
in vivo. Nat Med 1999;5:6628.
36. Green SK, Frankel A, Kerbel RS. Adhesion-dependent multicellular drug
resistance. Anticancer Drug Des 1999;14:15368.
37. Belotti D, Vergani V, Drudis T, Borsotti P, Pitelli MR, Viale G, et al. The
microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer
Res 1996;2:18439.
38. Lau DH, Xue L, Young LJ, Burke PA, Cheung AT. Paclitaxel (Taxol): an inhibitor of
angiogenesis in a highly vascularized transgenic breast cancer. Cancer Biother
Radiopharm 1999;14:316.
39. Laquente B, Vinals F, Germa JR. Metronomic chemotherapy: an antiangiogenic
scheduling. Clin Transl Oncol 2007;9:938.
40. Damber JE, Vallbo C, Albertsson P, Lennernas B, Norrby K. The anti-tumour
effect of low-dose continuous chemotherapy may partly be mediated by
thrombospondin. Cancer Chemother Pharmacol 2006;58:35460.
41. Sanchez-Munoz A, Mendiola C, Perez-Ruiz E, Rodriguez-Sanchez CA, Jurado JM,
Alonso-Carrion L, et al. Bevacizumab plus low-dose metronomic oral
cyclophosphamide in heavily pretreated patients with recurrent ovarian
cancer. Oncology 2010;79:98104.
42. Yang YI, Kim JH, Lee KT, Choi JH. Costunolide induces apoptosis in platinumresistant human ovarian cancer cells by generating reactive oxygen species.
Gynecol Oncol 2011;123:58896.
43. Cure H, Battista C, Guastalla JP, Fabbro M, Tubiana N, Bourgeois H, et al. Phase
III randomized trial of high-dose chemotherapy (HDC) and peripheral blood
stem cell (PBSC) support as consolidation in patients (pts) with advanced
ovarian cancer (AOC): 5-year follow-up of a GINECO/FNCLCC/SFGM-TC study. J
Clin Oncol: Off J Am Soc Clin Oncol 2004;22.
44. Kaye SB, Lewis CR, Paul J, Duncan ID, Gordon HK, Kitchener HC, et al.
Randomised study of two doses of cisplatin with cyclophosphamide in
epithelial ovarian cancer. Lancet 1992;340:32933.
45. Kaye SB, Paul J, Cassidy J, Lewis CR, Duncan ID, Gordon HK, et al. Mature results
of a randomized trial of two doses of cisplatin for the treatment of ovarian
cancer. Scottish Gynecology Cancer Trials Group. J Clin Oncol: Off J Am Soc Clin
Oncol 1996;14:21139.
46. Alberts DS, Liu PY, Hannigan EV, OToole R, Williams SD, Young JA, et al.
Intraperitoneal cisplatin plus intravenous cyclophosphamide versus
intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian
cancer. N Engl J Med 1996;335:19505.
47. Markman M, Bundy BN, Alberts DS, Fowler JM, Clark-Pearson DL, Carson LF,
et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus
moderately high-dose carboplatin followed by intravenous paclitaxel and
intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an
intergroup study of the Gynecologic Oncology Group, Southwestern Oncology
Group, and Eastern Cooperative Oncology Group. J Clin Oncol: Off J Am Soc Clin
Oncol 2001;19:10017.
48. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al.
Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med
2006;354:3443.
49. Friedlander M. Optimally debulked stage III ovarian cancer: intraperitoneal or
intravenous chemotherapy? Int J Gynecol Cancer: Off J Int Gynecol Cancer Soc
2010;20. S20-3.
50. Gore M, du Bois A, Vergote I. Intraperitoneal chemotherapy in ovarian cancer
remains experimental. J Clin Oncol: Off J Am Soc Clin Oncol 2006;24:452830.
51. Gordon AN, Tonda M, Sun S, Rackoff W. Long-term survival advantage for
women treated with pegylated liposomal doxorubicin compared with
topotecan in a phase 3 randomized study of recurrent and refractory
epithelial ovarian cancer. Gynecol Oncol 2004;95:18.
52. Excellence NIfHaC. Ovarian cancer (advanced) paclitaxel, pegylated liposomal
doxorubicin hydrochloride and topotecan (review); 2005.
53. Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as
second-line therapy for platinum-resistant and platinum-sensitive ovarian
carcinoma: a Gynecologic Oncology Group study. J Clin Oncol: Off J Am Soc Clin
Oncol 1998;16:40510.
54. van der Burg ME, de Wit R, van Putten WL, Logmans A, Kruit WH, Stoter G, et al.
Weekly cisplatin and daily oral etoposide is highly effective in platinum
pretreated ovarian cancer. Br J Cancer 2002;86:1925.
55. Mabel J. Therapeutic synergism in murine tumours for combination of cisdiamminedichloroplatinum with VP 16213 or BCNU. Proc Am Assoc Cancer Res
1979;20:230.
56. Chambers SK, Chambers JT, Kohorn EI, Schwartz PE. Etoposide (VP-16-213) plus
cis-diamminedichloroplatinum as salvage therapy in advanced epithelial
ovarian cancer. Gynecol Oncol 1987;27:23340.
57. Meyer T, Nelstrop AE, Mahmoudi M, Rustin GJ. Weekly cisplatin and oral
etoposide as treatment for relapsed epithelial ovarian cancer. Ann Oncol
2001;12:17059.
58. Piver MS, Lele S, Barlow J. Weekly cis-diamminedichloroplatinum(II): active
third-line chemotherapy in ovarian carcinomaa preliminary report. Cancer
Treat Rep 1980;64:137982.
59. Scotto V, Sbiroli C. Weekly cis-platinum as third line chemotherapy in
advanced ovarian carcinoma. Phase II study. Eur J Gynaecol Oncol 1991;12:513.
60. Bolis G, Scarfone G, Luchini L, Ferraris C, Zanaboni F, Presti M, et al. Response to
second-line weekly cisplatin chemotherapy in ovarian cancer previously
treated with a cisplatin- or carboplatin-based regimen. Eur J Cancer
1994;30A:17648.

160

D.J. Pinato et al. / Cancer Treatment Reviews 39 (2013) 153160

61. Fruscio R, Garbi A, Parma G, Lissoni AA, Garavaglia D, Bonazzi CM, et al.
Randomized phase III clinical trial evaluating weekly cisplatin for advanced
epithelial ovarian cancer. J Natl Cancer Inst 2011;103:34751.
62. Leunen K, Cadron I, Van Gorp T, Amant F, Berteloot P, Neven P, et al. Does
paclitaxelcarboplatin chemotherapy in a dose-dense regimen enhance
survival of BRCA-related ovarian cancer patients? Int J Gynecol Cancer: Off J
Int Gynecol Cancer Soc 2009;19:15014.
63. Gabra H. Dose density and altered scheduling of adjuvant chemotherapy in
ovarian cancer: teaching old dogs new tricks? Discov Med 2009;8:1404.
64. de Jongh FE, de Wit R, Verweij J, Sparreboom A, van den Bent MJ, Stoter G, et al.
Dose-dense cisplatin/paclitaxel. A well-tolerated and highly effective
chemotherapeutic regimen in patients with advanced ovarian cancer. Eur J
Cancer 2002;38:200513.
65. Van der Burg ME et al. Phase II study of weekly paclitaxel carboplatin in the
treatment of progressive ovarian cancer. J Clin Oncol 2004;22(14S):5058.
66. Cadron I, Leunen K, Amant F, Van Gorp T, Neven P, Vergote I. The Leuven
dose-dense paclitaxel/carboplatin regimen in patients with recurrent ovarian
cancer. Gynecol Oncol 2007;106:35461.
67. Katsumata N, Watanbe T, Mukai H, Kasamatsu T, Tsunematsu R, Yamada T, et al.
A phase II trial of weekly paclitaxel/carboplatin (TJ) as salvage chemotherapy in
patients with relapsed ovarian cancer. ASCO: Proc Am Soc Clin Oncol 2001;865.
68. Havrilesky LJ, Alvarez AA, Sayer RA, Lancaster JM, Soper JT, Berchuck A, et al.
Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent
ovarian and peritoneal cancer. Gynecol Oncol 2003;88:517.
69. Bolanos M, Borrega P, Gonzalez-Beca R, Arranz J, Velasco A, Perez MM, et al.
Weekly paclitaxel/carboplatinum as rst-line chemotherapy in late relapses of
epithelial ovarian cancer. A preliminary report on side effects. Proc Am Soc Clin
Oncol: ASCO 2001;20 abstr 870.
70. Watanabe Y, Nakai H, Ueda H, Hoshiai H. Evaluation of weekly low-dose
paclitaxel and carboplatin treatment for patients with platinum-sensitive
relapsed ovarian cancer. Gynecol Oncol 2005;96:3239.
71. Kikuchi A, Sakamoto H, Yamamoto T. Weekly carboplatin and paclitaxel is safe,
active, and well tolerated in recurrent ovarian cancer cases of Japanese women
previously treated with cisplatin-containing multidrug chemotherapy. Int J
Gynecol Cancer: Off J Int Gynecol Cancer Soc 2005;15:459.
72. Dunton CJ. Phase II Study of weekly paclitaxel and weekly carboplatinum in
recurrent platinum sensitive ovarian cancer. Proc Am Soc Clin Oncol 2003;22
abstr 1876.
73. Rose PG, Smrekar M, Fusco N. A phase II trial of weekly paclitaxel and every
3 weeks of carboplatin in potentially platinum-sensitive ovarian and peritoneal
carcinoma. Gynecol Oncol 2005;96:296300.
74. Ishikawa H, Fujiwara K, Suzuki S, Tanaka Y, Kohno I. Platelet-sparing effect of
paclitaxel in heavily pretreated ovarian cancer patients. Int J Clin Oncol
2002;7:3303.
75. Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB,
et al. Paclitaxel plus platinum-based chemotherapy versus conventional
platinum-based chemotherapy in women with relapsed ovarian cancer: the
ICON4/AGO-OVAR-2.2 trial. Lancet 2003;361:2099106.
76. Sharma R, Graham J, Mitchell H, Brooks A, Blagden S, Gabra H. Extended weekly
dose-dense paclitaxel/carboplatin is feasible and active in heavily pre-treated
platinum-resistant recurrent ovarian cancer. Br J Cancer 2009;100:70712.

77. Kaern J, Baekelandt M, Trope CG. A phase II study of weekly paclitaxel in

platinum and paclitaxel-resistant ovarian cancer patients. Eur J Gynaecol Oncol
2002;23:3839.
78. Rosenberg P, Andersson H, Boman K, Ridderheim M, Sorbe B, Puistola U, et al.
Randomized trial of single agent paclitaxel given weekly versus every three
weeks and with peroral versus intravenous steroid premedication to patients
with ovarian cancer previously treated with platinum. Acta Oncol
2002;41:41824.
79. Markman M, Blessing J, Rubin SC, Connor J, Hanjani P, Waggoner S. Phase II trial
of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian
and primary peritoneal cancers: a Gynecologic Oncology Group study. Gynecol
Oncol 2006;101:43640.
80. Kita T, Kikuchi Y, Takano M, Suzuki M, Oowada M, Konno R, et al. The effect of
single weekly paclitaxel in heavily pretreated patients with recurrent or
persistent advanced ovarian cancer. Gynecol Oncol 2004;92:8138.
81. Dunder I, Berker B, Atabekoglu C, Bilgin T. Preliminary experience with salvage
weekly paclitaxel in women with advanced recurrent ovarian carcinoma. Eur J
Gynaecol Oncol 2005;26:7982.
82. Boruta 2nd DM, Fowler Jr WC, Gehrig PA, Boggess JF, Walton LA, Van Le L.
Weekly paclitaxel infusion as salvage therapy in ovarian cancer. Cancer Invest
2003;21:67581.
83. Ghamande S, Lele S, Marchetti D, Baker T, Odunsi K. Weekly paclitaxel in
patients with recurrent or persistent advanced ovarian cancer. Int J Gynecol
Cancer: Off J Int Gynecol Cancer Soc 2003;13:1427.
84. Markman M, Hall J, Spitz D, Weiner S, Carson L, Van Le L, et al. Phase II trial of
weekly single-agent paclitaxel in platinum/paclitaxel-refractory ovarian
cancer. J Clin Oncol: Off J Am Soc Clin Oncol 2002;20:23659.
85. Linch M, Stavridi F, Hook J, Barbachano Y, Gore M, Kaye SB. Experience in a UK
cancer centre of weekly paclitaxel in the treatment of relapsed ovarian and
primary peritoneal cancer. Gynecol Oncol 2008;109:2732.
86. Lortholary A, Largillier R, Weber B, Gladieff L, Alexandre J, Durando X, et al.
Weekly paclitaxel as a single agent or in combination with carboplatin or
weekly topotecan in patients with resistant ovarian cancer: the CARTAXHY
randomized phase II trial from Groupe dInvestigateurs Nationaux pour lEtude
des Cancers Ovariens (GINECO). Ann Oncol: Off J Eur Soc Med Oncol/ESMO
2012;23:34652.
87. Hoekstra AV, Hurteau JA, Kirschner CV, Rodriguez GC. The combination of
monthly carboplatin and weekly paclitaxel is highly active for the treatment of
recurrent ovarian cancer. Gynecol Oncol 2009;115:37781.
88. Alvero AB, OMalley D, Brown D, Kelly G, Garg M, Chen W, et al. Molecular
mechanism of phenoxodiol-induced apoptosis in ovarian carcinoma cells.
Cancer 2006;106:599608.
89. Kelly MG, Mor G, Husband A, OMalley DM, Baker L, Azodi M, et al. Phase II
evaluation of phenoxodiol in combination with cisplatin or paclitaxel in
women with platinum/taxane-refractory/resistant epithelial ovarian, fallopian
tube, or primary peritoneal cancers. Int J Gynecol Cancer: Off J Int Gynecol Cancer
Soc 2011;21:6339.
90. Sharma R, Graham J, Blagden S, Gabra H. Sustained platelet-sparing effect of
weekly low dose paclitaxel allows effective, tolerable delivery of extended dose
dense weekly carboplatin in platinum resistant/refractory epithelial ovarian
cancer. BMC Cancer 2011;11:289.